CN1211351C - Alpha-amino acid amides, prepn. thereof and the therapeutic use thereof - Google Patents

Alpha-amino acid amides, prepn. thereof and the therapeutic use thereof Download PDF

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CN1211351C
CN1211351C CNB971966044A CN97196604A CN1211351C CN 1211351 C CN1211351 C CN 1211351C CN B971966044 A CNB971966044 A CN B971966044A CN 97196604 A CN97196604 A CN 97196604A CN 1211351 C CN1211351 C CN 1211351C
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CN1225625A (en
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P·奇斯
P·文图拉
M·德尔卡纳里
R·德范蒂
E·阿马尼
G·威尔蒂
C·皮特拉
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

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Abstract

The present invention relates to serinamide, glycinamide, alaninamide and phenylalaninamide derivatives of formula (I) wherein R, R', R1 and R2 are as defined in the disclosure. The compounds (I) are useful for the treatment of neurological diseases.

Description

Alpha-amino acid amides, its preparation method and therepic use thereof
The present invention relates to alpha-amino acid amides, its preparation method and contain their pharmaceutical composition.
More precisely, the present invention relates to the silk amide of general formula (I), G-NH2, alanimamides and phenylalanyl sulfonamide derivatives:
Figure C9719660400051
Wherein
R is the straight or branched alkyl; Cycloalkylalkyl; Selectivity is replaced by alkyl, halogen or haloalkyl on the ring arylalkyl or phenylalkyl; Selectivity is by condensing or the uncondensed aryl that alkyl, alkoxyl group, halogen or haloalkyl replace;
R ' is a hydrogen; Alkyl; Phenyl; Phenylalkyl;
R 1C for selectively acylating 1-C 4Hydroxyalkyl or phenylalkyl;
R 2Be hydrogen; Alkyl; Phenyl; Phenylalkyl;
Condition is when R is aryl, R 1Can be hydrogen or alkyl C 1-C 4
Unless otherwise, alkyl is preferably C 1-C 10Alkyl such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, 2-ethyl pentyl group, 1-ethyl heptyl, 1-Methyl Octyl, 4-heptyl.
Cycloalkylalkyl is preferably moieties and contains group such as the cyclopropyl methyl that 1-3 carbon atom and cycloalkyl moiety contain 3-7 carbon atom, cyclopentyl-methyl, cyclohexyl methyl, 1-(5-norbornene) ethyl.
Arylalkyl or phenylalkyl that selectivity replaces are preferably 2-naphthyl methyl, benzyl, styroyl, hydrocinnamyl, the benzene butyl, 3-(4-methyl-phenyl) propyl group, 3-(4-fluorophenyl) propyl group, 3-(4-chloro-phenyl-) propyl group, 3-(4-trifluoromethyl) propyl group, 3-phenyl-1-methyl-propyl, 2-phenyl-1-methylethyl, 3-phenyl-3-methyl-propyl group, the 1-phenylethyl.
Condense or the uncondensed aryl be preferably optionally by one or more alkoxyl groups, halogen or haloalkyl replace 1,2,3,4-tetrahydrochysene-2-naphthyl, 2-2,3-indanyl.
The C of acidylate 1-C 4Hydroxyalkyl is preferably the acetoxyl group alkyl, propionyloxy alkyl, 2-methyl-prop acyloxy alkyl, benzoyloxy alkyl.
One class preferred compound is wherein
R 1Be CH 2OH; R is C 3-C 10Alkyl, C 2-C 4Phenylalkyl, selectivity be by alkyl, alkoxyl group, halogen or haloalkyl replace 1,2,3,4-tetrahydrochysene-2-naphthyl or 2-2,3-indanyl; R ' is hydrogen or methyl and R 2Be hydrogen or methyl.
Particularly preferred the next compound is wherein
R 1Be CH 2OH; R for optionally by one or more alkoxyl groups, phenyl-(C that halogen, haloalkyl replace 2-C 3)-alkyl or 1,2,3,4-tetrahydrochysene-2-naphthyl or 2-2,3-indanyl; R ' and R 2Be hydrogen.
The second class preferred compound is wherein
R 1Be hydrogen or methyl, R be selectivity by one or more alkyl, alkoxyl group, halogen, haloalkyl replace 1,2,3,4-tetrahydrochysene-2-naphthyl or 2-2,3-indanyl, and R ' and R 2Be hydrogen.
The compounds of this invention can be organic or inorganic acid salt form.
They can contain one or more asymmetric c atoms in addition, so they can contain the form of mixtures of the multiple diastereomer of arbitrary ratio, contain the right racemic mixture form of enantiomorph of identical or different ratio, and the optical pure compound form is used.
The compounds of this invention can be used for treating chronic neurodegenerative disease, alzheimer's disease for example, and various dementias, Parkinson's disease is enjoyed and is prolonged a tarantism, or acute neurodegenerative damage as apoplexy and head damage; And treatment epilepsy and dysthymia disorders.
Prior art
GB patent 2048852 (Continental Pharma company) discloses 2-amino acetamide (being commonly referred to G-NH2) derivative, and it can be used for treating epilepsy, and treatment dyskinesia such as Parkinson's disease are treated dysmnesia and may be treated dysthymia disorders.
The mouse tonic convulsion that some compounds of having come into the open bring out bicuculline when with the administration of 10-100mg/kg oral dose shows anticonvulsant action.
2-n-pentyl amino acetamide (following finger nonproprietary name milacemide) and hydrochloride thereof are subjected to special research.
Milacemide is as the reference compound of test The compounds of this invention pharmacologically active.
EP-B1-0400495 (Farmitalia Carlo Erba) discloses the derivative that alpha-amino group methane amide N-phenylalkyl replaces.
The example of special preferred compound is the derivative that amino propionic acid amide (especially alanimamides and silk amide) and amino acetamide (G-NH2) N-phenylalkyl replace.Described compound has activity and can be used as antiepileptic drug central nervous system, Mirapexin, anti-neurodegeneration medicine, thymoleptic, soporific and antispasmodic.
The anti-convulsant activity of assessing compound mice convulsion that bicuculline or 3-thiohydracrylic acid are brought out.
Compound described in the EP-B1-0400495 also is potent monoamine oxidase (MAO) inhibitor.
WO94/22808 and WO94/22809 (Pharmacia/Farmitalia Carlo Erba) disclose the replacement of alkoxy aryl benzyl and other the amino propanamide derivative replacement of aryl-alkyl amino benzyl that acts on central nervous system respectively.
Among the WO94/22808 invention one of the most representative compound have active FCE28245 for claiming in the mouse electroshock is fainted from fear test, chemistry is called the 2-[4-[3-hydrocinnamyl] oxy-benzyl]-amino-3-hydroxyl propionic acid amide mesylate.
PCT n 0WO 95/18617 (Teva-Technion) and PCT n.WO96/21640 (Teva-Lemmon) have put down in writing amino benzo cycloalkane derivative of 1-such as 1-amino-1,2-indane and 1-amino-1,2,3, the 4-tetraline, it can be used for treating Parkinson's disease, dementia, disease after epilepsy and the wound.
Yet, more above-mentioned compounds such as racemize N-(2-kharophen)-1-amino-1,2-indane and optical activity form thereof; N-(2-kharophen)-6-fluoro-1-amino-1, the 2-indane; N-(2-kharophen)-1-amino-1,2,3,4-tetralin; N, N-two-(2-kharophen)-1-amino-1,2-indane and N-(2-propionamido)-1-amino-1, as if the 2-indane is not very effective in the anti-convulsant activity test, do not have particularly advantageous therapeutic index.
The alpha-amino acid amides that has now found that general formula (I) has more high-effect and/or better pharmacology curve than prior art compound.
The compounds of this invention can prepare by following method:
Make amino acid ester or the acid amides of formula II
Figure C9719660400081
R wherein 1As above definition, X is alkoxyl group or NHR 2Base, wherein R 2As above definition,
Compound reaction with formula III
Wherein Y is Sauerstoffatom or NH base, and R 3And R 4, identical or different, be hydrogen, or constitute above-mentioned radicals R or R together with the carbon atom that they connected 1One of, obtain formula IV compound
One or more reactions convert it into formula I compound below available then:
-when X is alkoxyl group, with formula R 2-NM 2Amine reaction;
-N-alkylation;
-R 1The acidylate of the middle any hydroxyl that exists;
-salify and/or optical resolution;
-remove any protecting group.
First embodiment of aforesaid method relate to Y wherein be oxygen the compound of formula III reduction amination wherein X be the formula II compound or its salt (being generally hydrochloride) of alkoxyl group such as methoxyl group, subsequently with formula R 2-NH 2Amine reaction.
In in organic solvent such as alcohol or acetonitrile, carrying out reduction amination according to a conventional method under 0-40 ℃ the temperature with stoichiometry or excessive slightly reagent.Hydrogen under hydride such as sodium cyanoborohydride or catalyzer such as Pd/ carbon exist can be used as reductive agent.
Be used in the water in room temperature or in chemical reactor under the heating condition or at organic solvent, particularly excessive amine carries out subsequently amidate action in methyl alcohol or the ethanol.
Second scheme relates to by stating method reduction amination Compound I I, and wherein X is R 2-NH base.
At last, the 3rd scheme relate to Y wherein be group with imine moiety (the being generally phenyl imine) III of NH change imido grpupization (transimination) wherein X be R 2The Compound I I of-NH-.In reacting at organic solvent under 0 °-40 ℃ the temperature as alcohol, methylene dichloride or acetonitrile.In organic solvent (being generally alcohol), making reductive agent reduction gained compound under the 0-40 ℃ of temperature subsequently with hydride such as sodium borohydride as ethanol or methyl alcohol.
In addition, but the also alpha-halogen ester of through type V
Figure C9719660400091
R wherein 1As above define and be preferably H, W is halogen atom (being generally chlorine or bromine) and R 5Be alkyl, with the amine condensation of formula VI
R wherein 3And R 4As above amine R is used in definition subsequently 2-NH 2Amidated prepares Compound I.Under 40 ° of-140 ℃ of temperature at organic solvent such as acetonitrile, alcohol, in the dimethyl formamide in the presence of acid binding agent such as the salt of wormwood and preferably in the presence of the catalytic amount potassiumiodide, carry out the condensation of compound V and compound VI.Carry out amidation by above-mentioned then.
The alpha-halogen acid amides also can with amine VI condensation.
Be the therepic use of imagination, Compound I will be formulated in the suitable pharmaceutical composition, and said composition is another purpose of the present invention.
Described composition generally contains 1-1000mg activeconstituents, particularly 10-100mg, and according to the pharmacokinetics of disease, selected activeconstituents and status of patient (body weight, sex, age) is administered once every day or repeatedly.
With for example at Remington ' s Pharmaceutical Sciences Handbook, Mack, Pub., N.Y., routine techniques described in the U.S.A. and vehicle prepare said composition, by oral, non-enteron aisle or rectum administration.Examples of formulations comprises tablet, capsule, syrup, granule, sterilizing injecting solution agent or suspensoid, suppository or the like.
Following embodiment further specifies the present invention.
Embodiment
Embodiment 1
A) The preparation of N-(3-phenyl propyl)-L-serine methyl ester hydrochloride
With L-serine methyl ester hydrochloride (0.9mol, 14g), (0.9mol is 9.1g) with 3-phenylpropionaldehyde (0.9mol for triethylamine, 12.1g) be dissolved in the anhydrous methanol (370ml) in the Parr bottle, in the presence of 10%Pd/C under 45psi hydrogenation till stopping to absorb hydrogen.
Leach catalyzer, evaporate to dryness filtrate under the vacuum.With methylene dichloride (500ml) dissolving irreducible oil, wash organic liquor with water, evaporate to dryness under the vacuum obtains pale yellow oil.
Be dissolved in ether (800ml), use the methanolic hydrochloric acid acidifying, obtain the product hydrochloride.Leach precipitation, dry under 45 ℃ of vacuum.
Output: 17.5g (71%)-fusing point=126-129 ℃.
B) (-)-(S)-3-hydroxyl-2-(3-phenyl propyl amino) propionamide hydrochloride (CHF 2803.01) preparation
(0.06mol, 17g) water-soluble (500ml) alkalizes to pH=8 with 10% wet chemical with the product that obtains in a).Use the dichloromethane extraction free alkali, evaporate to dryness under the vacuum.Gained light yellow oil (16.3g) is dissolved in methyl alcohol (150ml).Ammonia feeds in-5 ℃ of refrigerative solution to concentration and is about 15M.Room temperature (r.t.) seal systems reaction 5 days, evaporate to dryness under the vacuum then.Be dissolved in ethanol (40ml),,, obtain the product hydrochloride with ether (500ml) precipitation with ether HCl acidifying.
Filter white solid, in 40 ℃ of vacuum-dryings.
Output: 7.6g (46.5%)-fusing point: 153-155 ℃.
[α] 589(c=1, methyl alcohol)=-13.5
Embodiment 2
A) The preparation of N-(2-tetralyl)-D-serine methylester
To the beta-tetrahydro naphthalenone (0.068mol, 10.5g) and the D-serine methyl ester hydrochloride (0.07mol, 11g) add in the solution in 10/1 ethanol/methyl alcohol (550ml) sodium cyanoborohydride (0.07mol, 4.5g).Mixture is in room temperature reaction 24 hours, evaporated in vacuo, and water (800ml) dissolving is with ethyl acetate (2 * 500ml) extractions.With the 1N HCl (organic phase that 2 * 300ml) extractions merge.With the sodium bicarbonate water that alkalizes, with ethyl acetate (3 * 200ml) extractions.The organic phase that evaporated in vacuo merges obtains the yellow oily product.
Output: 12g (72%).
B) (R)-3-hydroxyl-2-(1,2,3, and 4-tetrahydrochysene-naphthalene-2-(R, S)-Ji amino) propionic acid amide (CHF2818) preparation
(concentration reaches about 15M for 0.048mol, methyl alcohol 12g) (150ml) solution in 0 ℃ the ammonia bubbling to be fed N-(2-tetralyl)-D-serine methylester.Tightness system was reacted under room temperature 120 hours.Evaporated in vacuo solution grinds in sherwood oil and makes irreducible oil curing.
Output: 9g (80%)-fusing point: 104-115 ℃
C) separation of CHF 2818 diastereomers
3-hydroxyl-2-(R)-(1,2,3,4-tetrahydrochysene-naphthalene-2-(S) base is amino) propionic acid amide The preparation of (CHF 2983)
With 2-(R)-(1,2,3,4-tetrahydrochysene-2-(R, S)-naphthyl amino)-3-hydroxyl propionic acid amide (0.038mol, 8.8g) crystallization in ethyl acetate (200ml), the gained solid is recrystallization twice in ethyl acetate (200ml), at last recrystallization in ethanol (50ml).In 45 ℃ of solid shape crystallizations of vacuum-drying white.
Output: 1.9g (productive rate 43%)-fusing point=142-145 ℃
[α] 589(c=1, methyl alcohol)=+ 92
D) 3-hydroxyl-2-(R)-(1,2,3,4-tetrahydrochysene-naphthalene-2-(R) base is amino) propionic acid amide hydrochloric acid The preparation of salt (CHF 2982.01)
First three the subcrystalline mother liquor that merges CHF 2983 was placed 48 hours at 0 ℃: leach precipitation, evaporated in vacuo filtrate.At room temperature development is solidified gained wax in ether (50ml).
(3M, 20ml) evaporate to dryness obtains the solid salt hydrochlorate, crystallization in 1/1 ethanol/ethyl acetate (400ml) then under middle dissolving and the vacuum at methyl alcohol HCl.Dry white crystalline solid under 45 ℃ of vacuum.
Output: 1.8g (36%)-fusing point=226-232 ℃
[α] 589(c=1, methyl alcohol)=-105.1
Embodiment 3
A) The preparation of 3-(4-aminomethyl phenyl) propionyl chloride
With 3-(4-aminomethyl phenyl) propionic acid (0.055mol, 9g) be dissolved in thionyl chloride (1.008mol, 120g).In stirring at room mixture 30 minutes, refluxed then 1 hour 30 minutes, vacuum-evaporation is to oily, with toluene and hexane dissolving, each evaporate to dryness.
Output: 12.4g
B) The preparation of 3-(4-aminomethyl phenyl) propionic aldehyde
With triphenylphosphine (0.117mol, 30.8g) solution in acetone (200ml) in room temperature under nitrogen gas stream with two-(triphenylphosphine)-tetrahydrochysene copper borate (I) (0.067mol, 40.69g) be added to together, in 45 minutes, drip then 3-(4-aminomethyl phenyl) propionyl chloride be dissolved in the acetone (85ml) (0.055mol, 10g).Under nitrogen, stirred the mixture 1 hour in room temperature.The solid of filtering-depositing is washed with acetone, evaporated in vacuo filtrate.Resistates is dissolved in chloroform (340ml), and adding chlorination, cuprous (0.135mol 13.38g), stirred 1 hour under nitrogen gas stream in room temperature.Use the diatomite filtration mixture, evaporate to dryness filtrate is dissolved in ether and sherwood oil with the gained resistates, filters, and vacuum-evaporation obtains oil.
Output: 6.7g (83%)
C) The preparation of 3-hydroxyl-2-(3-(4-aminomethyl phenyl)-propyl group amino) methyl propionate hydrochloride
With the methyl alcohol of 2% sodium (0.045mol, 51.7ml) liquid adds the D that is dissolved in the methyl alcohol (70ml), (0.045mol 7g), obtains free alkali to the L-serine methyl ester hydrochloride.
The sodium-chlor that forms precipitates with ether (150ml), and leaches.Evaporated in vacuo filtrate.The gained resistates is dissolved in methyl alcohol (450ml), and (0.045mol 6.7g), regulates pH to 6 with acetate, adds sodium cyanoborohydride, and mixture was in room temperature reaction 24 hours to add 3-(4-aminomethyl phenyl propionic aldehyde).With methyl alcohol HCl acidifying mixture, evaporated in vacuo, with methylene dichloride (600ml) dissolving, with the triethylamine alkalization, (3 * 500ml) wash water then.The evaporated in vacuo organic phase with ether (400ml) dissolving, with ether HCl acidifying, obtains the product hydrochloride.In 30 ℃ of vacuum-drying white solid precipitations.
Output: 8.8g (68%).
D) 3-hydroxyl-2-(3-(4-aminomethyl phenyl) propyl group amino) propionamide hydrochloride (CHF 2934.01) preparation
(0.03mol, 8.6g) water-soluble (500ml's methyl propionate hydrochloride) alkalizes to pH=8 with 10% wet chemical with 3-hydroxyl-2-(3-(4-aminomethyl phenyl) propyl group amino).Use the dichloromethane extraction free alkali, evaporated in vacuo.The pale yellow oil of gained (16.3g) is dissolved in methyl alcohol (150ml).To in-5 ℃ of refrigerative solution, blasting the ammonia bubble to about 15M concentration.Tightness system is in room temperature reaction 5 days, evaporated in vacuo then.Be dissolved in ethanol (40ml),, obtain the product hydrochloride with ether HCl acidifying and with ether (500ml) precipitation.Filter white solid, in 40 ℃ of vacuum-dryings.
Output: 4.9g (60%)-fusing point=173-176 ℃
Embodiment 4
A) The preparation of 4-phenyl butyryl chloride
With 4-phenyl-butyric acid (0.83mol, 13.57g) be added to thionyl chloride (0.114mol, 8.27ml) in, the dissolved solids of heating.In stirring at room mixture 30 minutes, refluxed then 10 minutes, press embodiment 3a at last) reclaim.
Obtain 100% productive rate (0.083mol, 15.09g).
B) The preparation of 4-phenyl butyraldehyde
Step from 4-phenyl butyryl chloride (0.083mol, 15.09g) beginning is according to 3b) obtains the 11g product.
C) (R)-preparation of 3-hydroxyl-2-(4-phenyl butyl amino) methyl propionate hydrochloride
With the methyl alcohol of 2% sodium (0.052mol, 59.8ml) liquid be added to the D-serine methyl ester hydrochloride that is dissolved in the methyl alcohol (81.6ml) (0.052mol, 8.16g) in to discharge alkali.(163ml) precipitates formed sodium-chlor with ether, leaches.Evaporated in vacuo filtrate.The gained resistates is dissolved in methyl alcohol (150ml), add 4-phenyl butyraldehyde (0.051mol 10.69g), regulates pH to 6 with acetate, add sodium cyanoborohydride (0.055mol, 3.62g), in room temperature reaction 24 hours.With methyl alcohol HCl acidifying mixture, evaporated in vacuo, be dissolved in methylene dichloride (600ml) and 1M sodium hydrogen carbonate solution.Be separated, (3 * 200ml) aqueous phase extracted once more wash the organic phase of merging, evaporated in vacuo then with water with methylene dichloride.Product restores and is hydrochloride, with ether (180ml) dissolving, with ether HCl acidifying.In 30 ℃ of sedimentary white solids of vacuum-drying.
Output: 5.83g (40%)
D) (R)-and 3-hydroxyl-2-(4-phenyl) butyl amino) preparation of propionic acid amide (CHF2918)
((0.02mol, 5.83g) water-soluble (250ml's hydroxyl-2-(4-phenyl butyl amino) methyl propionate hydrochloride) alkalizes with 10% aqueous sodium carbonate with (R)-3-.With methylene dichloride (3 * 200ml) extraction of free base, evaporated in vacuo.The gained light yellow oil is dissolved in methyl alcohol (150ml).To in-5 ℃ of refrigerative solution, blasting the ammonia bubble, to about 15M concentration.Tightness system was in room temperature reaction 5 days, and evaporated in vacuo obtains viscous crude then.With ether (25ml) dissolving and with hexane (400ml) precipitation, obtain solid shape product.Filter white solid, in 35 ℃ of vacuum-dryings.
Output: 4.43g (92%)-fusing point=59-61 ℃
With being similar to the compound 1-5 that method described in the embodiment 1-4 prepares table 1,27,28,30,33,34,38,39,42-44,46-48,52 and 53.
Embodiment 5
(R)-preparation of 3-hydroxyl-2-(3-phenyl propyl amino) propionic acid amide (CHF 2679)
With the D-silk amide (0.038mol, 4g) and the 3-phenylpropionaldehyde (0.038mol 5.1g) is dissolved in methyl alcohol (400ml) in the Parr bottle, and hydrogenation under 40psi in the presence of 10%Pd/C (3g) is till stopping to absorb hydrogen.Leach catalyzer, evaporated in vacuo solution, with ethyl acetate (300ml) dissolving, (2 * 200ml) wash water.Dry organic phase is dissolved in the warm ether (300ml), and slow evaporating solvent is settled out white solid product under room temperature.
Output: 3.8g (45%)-fusing point=76-78 ℃.
[α] 589(c=1, methyl alcohol)=+ 13.2 °
With being similar to the step described in the embodiment 5, the compound 6-13 of preparation table 1,15-22,24,26,49-51.
Embodiment 6
(R)-preparation of 2-(4-heptyl amino)-3-hydroxyl propionic acid amide phosphoric acid salt (CHF 2870.02)
The D-silk amide (0.01mol, 1g) and dipropyl ketone (0.01mol, 1.1g) solution in methyl alcohol (50ml) add 4M methyl alcohol HCl (0.0033mol, 0.85ml) and sodium cyanoborohydride (0.005mol, 0.33g).Mixture was in room temperature reaction 10 days, and HCl is acidified to pH=2 with methyl alcohol, evaporated in vacuo.Water (100ml) dissolution residual substance, (100ml) washes with ether, with the yellow soda ash alkalization, with chloroform (3 * 100ml) extractions.Gained oil (1.3g) is dissolved in methyl alcohol (50ml), and (0.0065mol 0.75g) handles, and evaporated in vacuo obtains extremely light solid foam shape product then with 85% phosphoric acid.
Output: 2g (77%)-fusing point=150-156 ℃
[α] 589(c=1, water)=+ 1.9
Embodiment 7
A) The preparation of 3-hydroxyl-2-(N-methyl-(3-phenyl-propyl group) amino) methyl propionate
N-(3-phenyl propyl) serine methylester (6.4g, 0.027mol) solution in methyl alcohol (150ml) add 10%Pd/C (0.7g) and be dissolved in methyl alcohol (50ml) 40% formaldehyde (3.0ml, 0.04mol).In stirring the mixture under room temperature low pressure (40psi) nitrogen atmosphere till stopping absorption.Filtering mixt, vacuum-evaporation filtrate.Resistates is dissolved in the ether (300ml), and (2 * 200ml) wash water, dry on sodium sulfate, vacuum-evaporation.Output: 6.6g.
B) Amino propionamide hydrochloride (the CHF of 3-hydroxyl-2-(N-methyl-3-phenyl-propyl group) 2968.01) preparation
Repeat the step of embodiment 3b.
((0.026mol blasts the ammonia bubble and is about 15M until concentration N-methyl-(3-phenyl propyl amino) methyl propionate in methyl alcohol 6.6g) (150ml) solution to 3-hydroxyl-2-in 0 ℃.System's reaction 120 hours in T～80 ℃ in closed reactor.Evaporated in vacuo solution obtains oil, therefrom isolates product by the low pressure liquid chromatography.Gained oil is dissolved in dehydrated alcohol and ethyl acetate, uses ether HCl acidifying then.Add diethyl ether, stir the mixture, leach precipitation then, in 40 ℃ of vacuum-dryings.
Output: 3.5g, fusing point: 112-114 ℃.
Prepare following compounds with being similar to embodiment 7 described steps:
(R)-3-hydroxyl-2-(N-methyl-2-2,3-indanyl amino) propionamide hydrochloride (CHF 3440.01, compound 63)
(S)-3-hydroxyl-2-(N-methyl-2-2,3-indanyl amino) propionamide hydrochloride (CHF 3462.01, compound 67).
Embodiment 8
A) The preparation of 2-(2,3-indanyl amino) methyl acetate
With glycine methyl ester (0.053mol 6.64g) is dissolved in dehydrated alcohol (420ml) and methyl alcohol (42ml), adds 2 in 40 minutes, 3-dihydro-2-indone (0.053mol, 7g) and under agitation add sodium cyanoborohydride (0.058mol, 3.7g).Mixture is placed under stirring at room and is spent the night, and evaporated in vacuo is with resistates water-soluble (500ml) and ethyl acetate (500ml).Be separated, with 0.1N HCl solution (3 * 200ml) extracted organic phase.To pH=8.5-9, (3 * 250ml) extract with ethyl acetate with saturated sodium bicarbonate solution adjustment of acidity solution.Separate organic solution, dry on sodium sulfate, vacuum-evaporation.In room temperature dry products therefrom under vacuum.
Output: 5.8g (53.4%)
B) The preparation of 2-(2-2,3-indanyl amino) acetamide hydrochloride (CHF 3381.01)
(0.028mol 5.8g) is dissolved in～methyl alcohol (150ml) solution of 15M ammonia, and in vitro places several days in sealing in room temperature with 2-(2,3-indanyl amino) methyl acetate.Evaporated in vacuo solution, be dissolved in dehydrated alcohol (2 * 200ml), each evaporation.Oil is dissolved in methyl alcohol (30ml) and under agitation is acidified to acid pH with the HCl absolute methanol solution.Add the ether sedimentation product, filter, dry under 45 ℃ of vacuum.
Output: 6.05g (94.6%)-fusing point=212-213 ℃
Embodiment 9
The preparation of 2-(N-methyl-2-2,3-indanyl amino) ethanamide (CHF3488)
With 2-(2-2,3-indanyl amino) ethanamide (0.016mol 3.00g) is dissolved in methyl alcohol (60ml), under agitation add salt of wormwood (0.016mol, 2.18g).In room temperature in 15 minutes to wherein drip methyl iodide (0.028mol, 4.14g).Mixture is in room temperature reaction 4 hours, vacuum-evaporation then.With gained solid water-soluble (100ml), with ethyl acetate (3 * 150ml) extraction water solution.Dry organic solution on sodium sulfate, vacuum-evaporation obtains oil then, in depress by silica gel (eluent chloroform: chromatographic separation methyl alcohol=90: 10).
Output: 1.31g (40%)-fusing point=122-123 ℃
Embodiment 10
A) (S)-preparation of 3-hydroxyl-2-(2-2,3-indanyl-amino) methyl propionate
With the L-serine methyl ester hydrochloride (0.05mol 7.78g) is dissolved in dehydrated alcohol (400ml) and methyl alcohol (40ml), under agitation adds 2 in 30 minutes, 3-dihydro-2-indone (0.05mol, 6.74g) and sodium cyanoborohydride (0.55mol, 3.64g).In stirring at room mixture 5 hours, evaporated in vacuo then was with resistates water-soluble (150ml) and ethyl acetate (150ml).Be separated, use ethyl acetate (200ml) aqueous phase extracted again.With the 0.2N HCl solution (organic phase that 2 * 200ml) extractions merge.Fractionate aqueous solutions is regulated pH=8 with sodium bicarbonate, with ethyl acetate (2 * 300ml) extractions.Separate organic solution, dry on sodium sulfate, vacuum-evaporation.Dry products obtained therefrom under the room temperature vacuum.
Output: 8.4g (71.4%).
B) (S)-3-hydroxyl-2-(2-2,3-indanyl amino)-propionamide hydrochloride (CHF 2993.01) preparation
With (S)-3-hydroxyl-2-(2-2,3-indanyl amino) methyl propionate (0.0357mol, 8.4g) be dissolved in～12M ammonia methyl alcohol (150ml) in and at room temperature in the sealing test tube, placed several days.Evaporated in vacuo solution obtains being dissolved in methyl alcohol (2 * 250ml) oil, each evaporate to dryness.Products obtained therefrom (alkali) is dissolved in ethyl acetate (170ml), and under agitation the 4.75N anhydrous ethyl acetate solution with HCl is acidified to acid pH.Filtering product, crystallization in dehydrated alcohol is in 40 ℃ of vacuum-dryings.
Output: 6.7g (72.8%)-fusing point=186-187 ℃
[α] 589(c=1, methyl alcohol)=+ 16.6 (hydrochloride)
[α] 589(c=1, methyl alcohol)=-24.6 (alkali)
Obtain mesylate (CHF 2993.02) with the prior art currently known methods.
Fusing point: 180-183 ℃
[α] 589(c=1, methyl alcohol)=+ 13.4
The compound 41,57,61,62,69,72,75 and 76 for preparing table 1 with similar approach described in the embodiment 10.
Embodiment 11
(S)-2-(2-2,3-indanyl amino)-3-(2-methyl-propionyl oxygen base) propionyl The preparation of amine hydrochlorate (CHF 3542.01)
With (S)-3-hydroxyl-2-(2-2,3-indanyl amino)-propionamide hydrochloride (CHF 2993.01, and 0.006mol 1.6g) is dissolved in trifluoroacetic acid (3.75ml), drip 2-methyl-prop acyl chlorides (0.022mol, 2.3ml).After the room temperature 2 hours, vacuum evaporated solution is dissolved in ether (100ml) with gained oil.Filtration product is ground in ether (50ml), filters and restores.In room temperature vacuum-drying solid.
Output: 1.8g (90%)-fusing point=171-174 ℃
Prepare following compounds with the method described in the similar embodiment 11:
(S)-3-acetoxyl group-2-(3-phenyl propyl amino) propionamide hydrochloride (CHF3023.01; Compound 45);
(S)-(CHF 3519.01 for propionamide hydrochloride for 3-acetoxyl group-2-(2-2,3-indanyl amino); Compound 74),
[α] 589(c=1, methyl alcohol)=+ 29.8
(S)-(CHF 3548.01 for propionamide hydrochloride for 3-benzoyloxy-2-(2-2,3-indanyl amino); Compound 78).
Embodiment 12
(S)-3-hydroxyl-2-(2-2,3-indanyl amino)-N-methyl propanamide hydrochloric acid The preparation of salt (CHF 3422.01)
(0.025mol 5.95g) is dissolved in the solution of 8.03M methylamine ethanol (155ml) in airtight test tube with N-(2-2,3-indanyl amino)-(S)-serine methylester.After 1 day, vacuum evaporated solution, (3 * 100ml), (fraction 40-70,100ml) dissolving gained oil evaporates sherwood oil at every turn with methyl alcohol.Gained oil under agitation solidifies with sherwood oil (250ml) dissolving.With filtering solid (～5.42g) be dissolved in the ethyl acetate (250ml) of tepor, under agitation add HCl anhydrous ethyl acetate (3.5M) up to obviously being acid pH.Filtration product, (150ml) repeats to wash with ether, at the vacuum oven inner drying.
Output: 5.33g (77.9%)-fusing point=190.5-192 ℃
[α] 589(c＝1，DMSO)＝+18
[α] 589(c=1, methyl alcohol)=-2
Prepare compound 55,56,58,60,64-66 with the method that is similar among the embodiment 12.
Embodiment 13
A) 5, the preparation of 6-dimethoxy-2-oxyimino-indone
With 5, (0.078mol 15g) is dissolved in 50 ℃ of homothermic dehydrated alcohols (550ml) 6-dimethoxy-1-indone, and (0.086mol is 11.9ml) with dense HCl (11.9ml) to add Isopentyl nitrite.Several minutes after product precipitation.React on 50 ℃ and kept 3 hours, cooling is at room temperature washed with dehydrated alcohol (50ml) and ether (100ml) then, crosses filter solid.In room temperature vacuum oven inner drying product.
Output: 16.3g (94.4%)
B) 5,6-dimethoxy-2-2, the preparation of 3-hydrindenyl amine
5, (0.27mol 6g) adds 96% sulfuric acid (3.3ml) and 10%Pd/C (1.5g) to 6-dimethoxy-2-oxyimino-1-indone in the solution in glacial acetic acid (500ml).At Pa Er equipment (room temperature, 35psi) middle hydrogenated mixture.When stopping to absorb hydrogen, leach catalyzer by diatomite, (70ml) washes with methyl alcohol.Evaporate to dryness solution obtains water-soluble white solid, uses ethyl acetate (2 * 70ml) extractions then.Alkalize the aqueous solution to pH=8-8.5 with the 1M sodium hydroxide solution.With methylene dichloride (2 * 70ml) extraction products.Dry organic solution on sodium sulfate, vacuum-evaporation obtains solid phase prod.
Output: 4.6g (88.5%)
C) 2-(5,6-dimethoxy-2-2,3-indanyl amino) ethanamide (CHF 3511) Preparation
With 5,6-dimethoxy-2-2, the 3-hydrindenyl amine (0.024mol, 4.6g) and sodium bicarbonate (0.026mol, (0.024mol 2.2g) in the solution in dehydrated alcohol (100ml), refluxed 10 hours 2.2g) to be added to chloro-acetamide.At the room temperature filtering mixt, evaporate to dryness solution.By silica gel medium pressure chromatogram (eluent: methylene chloride=90/10) separating obtained oil.
Output: 1.95g (32.7%)-fusing point=135-138 ℃
Method prepares following compounds described in the embodiment 13 with being similar to:
2-(5-fluoro-2-2,3-indanyl amino) acetamide hydrochloride (CHF3480.01);
2-(5,6-two fluoro-2-2,3-indanyl amino) acetamide hydrochloride (CHF3518.01).
In follow-up table 1, the abbreviation of embodiment compound and structural formula have been reported and the abbreviation and the structural formula of other compound of obtaining with above-mentioned same procedure.
Table 1
Alpha-amino acid amides derivative-structure
R ' is H, unless otherwise specified.
Compound R R1 R 2 Stereochemistry Compound number
CHF 2043 CHF 2088 CHF 2102 CHF 2452.01 CHF 2525.01 CHF 2545 CHF 2560 CHF 2571 CHF 2583 CHF 2597 CHF 2617 CHF 2621.01 CHF 2678 CHF 2679 (CH 2) 6CH 3 (CH 2) 4CH 3 (CH 2) 6CH 3 (CH 2) 4CH 3 (CH 2) 6CH 3 CH(CH 3) 2 CH(CH 3) 2 (CH 2) 6CH 3 CH 2-cyclohexyl (CH 2) 2CH 3 (CH 2) 6CH 3 CH(CH 3)(CH 2) 5CH 3 (CH 2) 2C 6H 5 (CH 2) 3C 6H 5 CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH CH 2C 6H 5 CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH H H H H H H H H H H (CH 2) 6CH 3H H H RS R R S S R S RS R S R R R R 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Figure C9719660400211
Compound R R1 R 2 Stereochemistry Compound number
CHF 2993.01 CHF 2996 CHF 3009.01 CHF 3010.01 CHF 3011.01 CHF 3023.01 CHF 3066 2-2, the 3-indanyl " 1; 2; 3,4-tetrahydrochysene-2-naphthyl " 2-naphthyl methyl (CH 2) 3-C 6H 56-Meo-1,2,3,4-tetrahydrochysene-2-naphthyl CH 2OH CH 2OH CH 3 CH 3 CH 2OH CH 2OAc CH 2OH H H H H H H H S R S RS R RS RS S R RS 40 41 42 43 44 45 46
Compound R R1 R 2 Stereochemistry Compound number
CHF 3091.01 CHF 3107.01 CHF 3145.01 CHF 3186.01 CHF 3189.01 CHF 3195.01 2-2,3-indanyl 3-(4-CF 3-phenyl)-and propyl group 1,2,3,4-tetrahydrochysene-2-naphthyl C 6H 5(CH 2) 3 C 6H 5(CH 2) 3 C 6H 5(CH 2) 3 R′＝C 6H 5-CH 2 CH 3 CH 2OH CH 2OH CH 2OH CH 2OH CH 2OH H H C 6H 5CH 2 C 6H 5CH 2 CH 3(CH 2) 4 H RS R R RS R R R 47 48 49 50 51 52
Compound R R1 R 2 Stereochemistry Compound number
CHF 3293 CHF 3381.01 CHF 3394.01 CHF 3408.01 CHF 3414.01 CHF 3421.01 CHF 3422.01 CHF 3427.01 (CH 2) 3-C 6H 5R '=normal-butyl 2-2,3-indanyl " " 1,2,3,4-tetrahydrochysene-2-naphthyl 2-2,3-indanyl " " CH 2OH H CH 2OH H H CH 3 CH 2OH CH 3 H H CH 3 CH 3 H CH 3 CH 3 CH 3 R - R - RS R S S 53 54 55 56 57 58 59 60
Compound R R1 R 2 Stereochemistry Compound number
CHF 3431.01 CHF 3434.01 CHF 3440.01 CHF 3441.01 CHF 3442.01 CHF 3443.01 CHF 3462.01 CHF 3480.01 CHF 3486.01 2-2,3-indanyl " " R '=CH 31,2,3,4-tetrahydrochysene-2-naphthyl " " 2-2,3-indanyl R '=CH 35-F-2-2, the 3-indanyl " CH 3 CH 3 CH 2OH H CH 2OH CH 2OH CH 2OH H CH 2OH H H H CH 3 CH 3 CH 3 H H H S R R RS R R S R S RS S RS 61 62 63 64 65 66 67 68 69
Compound R R1 R 2 Stereochemistry Compound number
CHF 3488 CHF 3511 CHF 3512.01 CHF 3518.01 CHF 3519.01 CHF 3531.01 CHF 3539.01 CHF 3542.01 CHF 3548.01 2-2,3-indanyl R '=CH 35,6-Meo-2-2,3-indanyl " 5; 6-F-2-2; 3-indanyl 2-2; 3-indanyl 5-Meo-2-2; 3-indanyl " 2-2,3-indanyls " H H CH 2OH H CH 2OAc H CH 2OH CH 2OOC-iPr CH 2OOC-C6H5 H H H H H H H H H - - S - S RS S RS S S 70 71 72 73 74 75 76 77 78
Anti-convulsant activity
For the potential anti-convulsant activity of research The compounds of this invention is estimated The compounds of this invention with some pharmacological testings.For this reason, with maximal electroshock (MES) experiment sieving compound.This model is widely used in the usefulness of estimating anti-whole body of antiepileptic drug and local epileptic seizures.With people such as W.Losher, EpilepsyRes., 2 (1988), the experimental technique of describing among the 145-181 carries out the research to rat and mouse.In brief, by the electricity irritation body between Corneal electrode by 0.2 second of 60Hz alternating-current (mouse 50mA, rat 150mA).The ED that suppressed THE at the most in 180 minutes by calculating was arrived in administration (oral) in back 60 minutes 50Measure the anticonvulsion usefulness of compound.Each dosage is used many groups of 10 animals, according to Litchfield and Wilcoxon (J.Pharmacol.Exp.Ther., 96 (1949), 99-113) calculate ED by amount-effect curve 50
In rat MES model, only estimate the time course of anti-convulsant activity.Before electroshock 30,60,120,240, handled each group of every group of 10 rats in 360 and 480 minutes with its isoreactivity dosage.Estimate anti-convulsant activity peak value and action period then.
Water plain net sieve test in another serial experiment that mouse is carried out (people such as L.L.Coughenour, Pharmacol.Bioch.and Behav., 6 (1977), 351-353) by the neurotoxicity of measuring impaired motor functional evaluation compound.In this model, mouse is placed in square metal wire mesh screens (squire wire screen) top respectively, and this mesh screen level is installed on the metal bar, and Rotate 180 ° makes mouse be positioned at the bottom of mesh screen then.Observe the damage of motor function from fall the number of animals that maybe can not climb to the mesh screen top by mesh screen.As above calculate half neurotoxicity dosage (TD then 50).TD 50With ED 50Ratio be called the therapeutic index (T.I.) of each compound.T.I. be used to show the useful differentiation of neurotoxicity and antiepileptic activity.Therapeutic index is big more, shows that above-mentioned active difference is big more, and the anticonvulsant drug curve is good more.
In mouse MES model, all are examined compound and all demonstrate the anti-convulsant activity of representing with mol that is better than milacemide and/or Sodium Valproate and tire.ED 50Value is 4.5-35 to milacemide potency ratio scope between 1.2-0.5mmol/kg, is 1-6.7 to Sodium Valproate potency ratio scope.
The evaluation of anti-convulsant activity time course shows that some compounds absorb rapidly, peak effect occurred in 30 minutes after the administration, and other compound has the effect that more delays, even just reaches the peak after the administration in 3 hours.
The common trait of a lot of compounds is to suppress the good durability of convulsions effect, and administration still had more than or equal to 50% after 3 hours has statistical significance.
Be longer than the action period (about 1 hour) of milacemide action period.
The more representative compound administration of the present invention after 60 minutes the MES test-results to mouse be shown in following table 2.
Compared The compounds of this invention activity and the activity that is recorded in two kinds of prior art compounds of WO 94/22808 and WO95/18617 respectively: FCE 28245, prototype with a series of novel serine derivatives of anti-convulsant activity, with TEVA compound 2 (1-amino-1,2-indane derivatives)
Compd E D 50MES TD 50Horizontal mesh screen T.I.
(CHF) (mg/kg is oral) (mg/kg is oral)
2993 44 1172 27
2996 34 ＞1500 44
2983 43 1300 30
2991 38 1099 29
3431 22 251 11
3440 35 689 20
3381 21 274 13
FCE 28245 180 1670 9
TEVA compound 2 38 299 8
T.I.: therapeutic index.
All compounds are all with the administration of HCl salt form.2-amino-1, each enantiomorph of 2-indane and amino-1,2,3,4-tetralin derivative shows significant anti-convulsant activity.(S)-and hydroxyl-2-amino-1,2-indane derivatives CHF 2993 and enantiomorph (R) CHF2996 thereof equivalence in the MES test.Back one compound is low (oral＞as 1500mg/kg) also to show higher therapeutic index (44) because of its neurotoxicity.Introduce methyl in the part of CHF2993 and obtain a kind of compound (CHF3440), it has identical anti-convulsant activity, but neurotoxicity increases (TD 50=689).On the contrary, (S)-2-(2-2,3-indanyl amino) propionic acid amide and 2-(2-2,3-indanyl amino) acetamide derivative CHF3431 and CHF3381 suppressing more effective on the MES, but than aforesaid compound neurotoxicity height.To 3-hydroxyl-2-1,2,3,4-tetraline sulfonamide derivatives CHF2983 (R, S enantiomorph) and CHF2991 (S, R enantiomorph) also observe good anti-convulsant activity curve.
All test-compound usefulness are FCE28245, and promptly about 3-4 of 3-hydroxyl-2-(4-(3-phenyl propyl oxygen base) benzyl amino) propionic acid amide mesylate usefulness doubly.
Also it should be noted that 2-amino-1,2-indane derivatives CHF 3381 is than known 1-amino-1 among the prior art WO 95/18617,2-indane compound 2, and promptly (S)-2-(2,3-indanyl amino) ethanamide has higher therapeutic index.In fact 2-amino-1 of the present invention, 2-indane compound is as the 1-amino-1 of anticonvulsive agent than prior art, and the 2-indane is more effective.These results are combined as can be seen, and 2-amino-1 of the present invention, 2-indane compounds are compared the motor that shows still less and are coordinated damage with the prior art compound.
To mouse MES test further, according to people such as Swinyard E.A., Antiepileptic Drug, the 3rd edition, Raven Press, method described in the New York (1989) is also estimated some compounds with rat MES test with by the tonic convulsion chemical model that bicuculline causes.In this model, observed mouse 30 minutes after the subcutaneous bicuculline that gives doses, cause 97% animal and tonic convulsion occurs.To animal with compound treatment, terminal point is used as in the disappearance of back leg tonic extension constituent element, show the capable prevention outbreak of examined object matter diffusion.
Disclosed FCE26743 (S)-2-(4-(3-fluorine benzyl amino) benzyl amino) propionic acid amide is as reference compound among the use prior art EP-B1-0400495.
The results are shown in following table 3:
Compd E D 50Active peak ED action period of MES 50The bicuculline mouse
(CHF) (MG/KG is oral) (hrs) *(hrs) *(mg/kg is oral)
2993 31 3 6 65
2996 32 1 2 n.t.
2983 19 1 2 62
FCE 26743 11 0.5 1 20
*: the maximum utility time
*: protection still has the time of statistical significance
N.t.: not test (N.T.)
In rat MES test, CHF2993, CHF2996 and FCE26743 show the anti-convulsant activity close with the mouse same model.CHF2983 is more effective in this test, oral ED 50Be 19mg/kg, be lower than report value among the mouse MES.Pharmacodynamics analysis revealed CHF2993 action period the longest (6 hours).Under any circumstance all be longer than the action period (1 hour) of reference compound FCE26743 the action period of all test-compounds.To the mice convulsion that bicuculline causes, oral CHF2993, the ED of CHF2983 and FCE26743 50Be respectively 65,62 and 20mg/kg.Though these values are higher than income value in the mouse MES test, these are worth still in the same order of its MES anti-convulsant activity effect.
These results are combined, and we may safely draw the conclusion: compound described here still all demonstrates significant anti-convulsant activity in the mice convulsion model that bicuculline causes in rat and mouse MES model.The activity that these compounds show mouse almost is similar to the activity of some standard antiepileptic drugs that comprise Phenytoin Sodium Salt, Carbamzepine, and be 4 times of Sodium Valproate at least, data in literature proves that those compounds compare with data of the present invention and have less therapeutic index.
The compounds of this invention can various formulation administrations, and for example oral with tablet, capsule, sugar or film garment piece, liquor agent form, with the suppository form rectal administration, parenterai administration is intramuscularly or intravenous injection or infusion for example.The treatment plan of different clinical syndromes must adapt to the histological type of common consideration, route of administration, compound administration formulation and patient's age, body weight and the state of an illness.
The treatment significant quantity is extremely approximately 1000mg of about 1mg in a scheme, and preferably approximately 10mg is to about 300mg.
Certainly, can adjust these dosages to reach optimum therapeutic response.
The character that contains the pharmaceutical composition of The compounds of this invention and pharmaceutically acceptable carrier or thinner depends on required route of administration certainly.
Available component commonly used is compositions formulated in the usual way.For example The compounds of this invention can water or oily solution, suspensoid, tablet, pill, gelatine capsule, syrup, drops or suppository form administration.
Therefore, concerning oral administration, the pharmaceutical composition that contains The compounds of this invention is preferably tablet, pill or gelatin, and it contains active substance and thinner such as lactose, glucose, sucrose, mannitol, Sorbitol Powder, Mierocrystalline cellulose; Lubricant such as silica, talcum, stearic acid, Magnesium Stearate or calcium stearate, and/or polyethylene glycols; Or they also can contain tackiness agent such as starch, gelatin, methylcellulose gum, carboxymethyl cellulose, Sudan Gum-arabic, tragacanth gum, polyvinylpyrrolidone; Disintegrating agent such as starch, alginic acid, alginate, sodium starch glycollate; Effervescent mixture; Dyestuff; Sweeting agent; Wetting agent such as lecithin, Spheron MD 30/70, dodecyl sulfate; And generally be used for the nontoxic of pharmaceutical preparation and parmacodynamics-less activity material.Can produce this pharmaceutical preparation by currently known methods, for example by mixing, granulation, compressing tablet, be coated with sugar or the mode of filming.
The liquid oral dispersion agent for example can be syrup, emulsion agent and suspensoid.
Syrup for example can contain sucrose or sucrose and glycerine and/or mannitol and/or Sorbitol Powder as carrier.Suspensoid and emulsion agent can contain for example natural gum, agar, and sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose, or polyvinyl alcohol is as carrier.The suspensoid of intramuscularly or solution can contain active compound and pharmaceutically acceptable carrier such as aqua sterilisa, sweet oil, and ethyl oleate, dibasic alcohol such as propylene glycol, if desired and the appropriate hydrochloric acid lignocaine.
The solution of intravenous injection or infusion for example can contain aqua sterilisa and make carrier, or preferably they for etc. ooze sterile saline solution form.
Suppository can contain active compound and pharmaceutically acceptable carrier such as theobroma oil, polyoxyethylene glycol, polyoxyethylene sorbitan fatty acid ester tensio-active agent or lecithin.

Claims (7)

1. formula I compound:
Figure C971966040002C1
Wherein
R 1Be hydrogen or methyl;
R is optionally by 1,2,3 of one or more alkyl, alkoxyl group, halogen or haloalkyl replacement, 4-tetrahydrochysene-2-naphthyl or 2-2,3-indanyl; And
R ' and R 2Be hydrogen.
2. prepare the method for the compound of claim 1, it comprises amino acid ester or the acid amides that makes formula II
Figure C971966040002C2
R wherein 1As above definition, X is alkoxyl group or NHR 2Base, wherein R 2As above definition,
Compound reaction with formula III
Figure C971966040002C3
Wherein Y is Sauerstoffatom or NH base, and R 3And R 4Radicals R with constituting with the carbon atom that they connected as defined in claim 1 obtains formula IV compound
One or more reactions convert it into formula I compound below available then:
-when X is alkoxyl group, with ammonia react;
-N-alkylation;
-salify and/or optical resolution;
-remove any protecting group.
3. the method for preparing the compound of claim 1,
It comprises the α halogen ester of formula V
R wherein 1As definition in the claim 1, W is a halogen atom, R 5Be alkyl,
Amine condensation with formula VI
Figure C971966040003C3
R wherein 3And R 4As definition in the claim 2,
Use the aminoacyl amination subsequently,
Obtain formula (I) compound.
4. the method for claim 3, wherein R 1Be H.
5. the method for claim 3, wherein W is a chlorine or bromine.
6. pharmaceutical composition, it contains as the compound of a kind of claim 1 of activeconstituents and appropriate excipients or carrier.
7. the compound of claim 1 is used to prepare the purposes of the medicine for the treatment of neurodegenerative disease.
CNB971966044A 1996-07-23 1997-07-15 Alpha-amino acid amides, prepn. thereof and the therapeutic use thereof Expired - Fee Related CN1211351C (en)

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US20030035784A1 (en) * 2001-03-05 2003-02-20 Kao Corporation Hair cosmetic, aminocarboxylic acid amide and method for producing the same
DE60122541T2 (en) * 2001-12-21 2007-09-13 Chiesi Farmaceutici S.P.A. 2-Indanylaminoderivate for the treatment of chronic, acute or inflammatory pain
FR2843590B1 (en) * 2002-08-14 2007-10-05 Prestwick Scient Capital Inc DERIVATIVES OF R (+) - 2-AMINO-3-HYDROXYPROPANOIC ACID WITH GLYCINERGIC ACTION
US20040082543A1 (en) * 2002-10-29 2004-04-29 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and NMDA receptor antagonists for the treatment or prevention of neuropathic pain
AU2005270949B2 (en) * 2004-08-03 2011-02-03 Chiesi Farmaceutici S.P.A. Derivatives of 1-phenylalkanecarboxylic acids for the treatment of neurodegenerative diseases
WO2014178083A1 (en) 2013-05-03 2014-11-06 Council Of Scientific & Industrial Research An improved synthesis of anti-parkinson agent
CN105646252A (en) * 2016-02-25 2016-06-08 吉尔生化（上海）有限公司 Synthesis method of H-SER-NH2*HCL
CN114051496B (en) * 2019-06-25 2023-08-04 阿米蒂比奥有限公司 Derivative compounds for introducing biphenyl into novel amino alkanoic acids and antifungal pharmaceutical compositions containing the same
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